In excitable cells, voltage-gated K+ channels play an important role in regulating the duration of the action potential. The long-term objective of our research program is to elucidate the mechanisms that regulate cardiac cell excitation. We hypothesize that the cardiac myocytes can respond to prolongation of action potential duration (ADP) by turning on the expression of potassium channel genes that shorten the repolarization period. This compensatory response may be a key to limiting the extent of the prolongation of the ADP and QT intervals. The aims of this proposal are to create mouse models to study electrical remodeling and elucidate the molecular mechanisms that control and regulation the expression of cardiac voltage-gated potassium channel genes. Specifically, the plan over the next five years is: (1) To create mouse models with combined deficiency of several outward potassium currents and to elucidate the molecular basis of the reentrant arrhythmias observed in mice over- expressing KV1.1N206Tag in the heart. (2) To elucidate the mechanisms which regulate the tissue-specific and the level of expression of Kv1.5. To characterize two novel transcription factors (KBF1 and KBF2) that bind to a silencer element (KRE) located in the promoter of Kv1.5. (3) To assess the biological role of KBF1 and KBF2 in the heart. In addition to contributing to our understanding of the basic mechanisms underlying cardiac excitation, these studies may be relevant to the development of new therapy to long QT syndrome and cardiac arrhythmias.